{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:19:09Z","timestamp":1788455949666,"version":"build-2803163510"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pharmacol Toxicol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The emergence and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in thelate 2019 has caused a devastating global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19). Although vaccines have been and are being developed, they are not accessible to everyone and not everyone can receive these vaccines. Also, it typically takes more than 10\u2009years until a new therapeutic agent is approved for usage. Therefore, repurposing of known drugs can lend itself well as a key approach for significantly expediting the development of new therapies for COVID-19.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We have incorporated machine learning-based computational tools and in silico models into the drug discovery process to predict Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of 90 potential drugs for COVID-19 treatment identified from two independent studies mainly with the purpose of mitigating late-phase failures because of inferior pharmacokinetics and toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we summarize the cardiotoxicity and general toxicity profiles of 90 potential drugs for COVID-19 treatment and outline the risks of repurposing and propose a stratification of patients accordingly. We shortlist a total of five compounds based on their non-toxic properties.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for treating COVID-19.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40360-021-00519-5","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T04:03:13Z","timestamp":1634788993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Computational determination of toxicity risks associated with a selection of approved drugs having demonstrated activity against COVID-19"],"prefix":"10.1186","volume":"22","author":[{"given":"Maral","family":"Aminpour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Williams Ernesto Miranda","family":"Delgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soren","family":"Wacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Noskov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Houghton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Lorne J.","family":"Tyrrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A.","family":"Tuszynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"issue":"7836","key":"519_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2951-z","volume":"588","author":"P Zhou","year":"2020","unstructured":"Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. Addendum: a pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;588(7836):E6. https:\/\/doi.org\/10.1038\/s41586-020-2951-z.","journal-title":"Nature."},{"issue":"3","key":"519_CR2","doi-asserted-by":"publisher","first-page":"105924","DOI":"10.1016\/j.ijantimicag.2020.105924","volume":"55","author":"C-C Lai","year":"2020","unstructured":"Lai C-C, Shih T-P, Ko W-C, Tang H-J, Hsueh P-R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents. 2020;55(3):105924. https:\/\/doi.org\/10.1016\/j.ijantimicag.2020.105924.","journal-title":"Int J Antimicrob Agents"},{"issue":"6","key":"519_CR3","doi-asserted-by":"publisher","first-page":"e46","DOI":"10.1016\/S2213-2600(20)30216-2","volume":"8","author":"RJ Jose","year":"2020","unstructured":"Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. 2020;8(6):e46\u20137. https:\/\/doi.org\/10.1016\/S2213-2600(20)30216-2.","journal-title":"Lancet Respir Med"},{"issue":"1","key":"519_CR4","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1177\/1740774517727742","volume":"15","author":"GK Gresham","year":"2018","unstructured":"Gresham GK, Ehrhardt S, Meinert JL, Appel LJ, Meinert CL. Characteristics and trends of clinical trials funded by the National Institutes of Health between 2005 and 2015. Clin Trials. 2018;15(1):65\u201374. https:\/\/doi.org\/10.1177\/1740774517727742.","journal-title":"Clin Trials"},{"issue":"7","key":"519_CR5","doi-asserted-by":"publisher","first-page":"2096","DOI":"10.1039\/C5MB00306G","volume":"11","author":"Y Yeu","year":"2015","unstructured":"Yeu Y, Yoon Y, Park S. Protein localization vector propagation: a method for improving the accuracy of drug repositioning. Mol BioSyst. 2015;11(7):2096\u2013102. https:\/\/doi.org\/10.1039\/C5MB00306G.","journal-title":"Mol BioSyst"},{"key":"519_CR6","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.curtheres.2017.01.007","volume":"84","author":"H Sweiti","year":"2017","unstructured":"Sweiti H, Ekwunife O, Jaschinski T, Lhachimi SK. Repurposed therapeutic agents targeting the Ebola virus: a systematic review. Curr Ther Res Clin Exp. 2017;84:10\u201321. https:\/\/doi.org\/10.1016\/j.curtheres.2017.01.007.","journal-title":"Curr Ther Res Clin Exp"},{"issue":"2","key":"519_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0245962","volume":"16","author":"JD Baker","year":"2021","unstructured":"Baker JD, Uhrich RL, Kraemer GC, Love JE, Kraemer BC. A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease. PLoS One. 2021;16(2):e0245962. https:\/\/doi.org\/10.1371\/journal.pone.0245962.","journal-title":"PLoS One"},{"issue":"11","key":"519_CR8","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/j.molmed.2016.09.006","volume":"22","author":"F Cheng","year":"2016","unstructured":"Cheng F, Murray JL, Rubin DH. Drug repurposing: new treatments for Zika virus infection? Trends Mol Med. 2016;22(11):919\u201321. https:\/\/doi.org\/10.1016\/j.molmed.2016.09.006.","journal-title":"Trends Mol Med"},{"issue":"7827","key":"519_CR9","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41586-020-2577-1","volume":"586","author":"L Riva","year":"2020","unstructured":"Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020;586(7827):113\u20139. https:\/\/doi.org\/10.1038\/s41586-020-2577-1.","journal-title":"Nature."},{"issue":"7816","key":"519_CR10","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","volume":"583","author":"DE Gordon","year":"2020","unstructured":"Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459\u201368. https:\/\/doi.org\/10.1038\/s41586-020-2286-9.","journal-title":"Nature."},{"key":"519_CR11","first-page":"469","volume":"32","author":"J Zupan","year":"1995","unstructured":"Zupan J. Neural networks in chemistry. Angew Chem Int Ed Engl. 1995;32:469\u201370.","journal-title":"Angew Chem Int Ed Engl"},{"key":"519_CR12","volume-title":"Statistical learning theory","author":"V Vapnik","year":"1998","unstructured":"Vapnik V. Statistical learning theory. New York: Wiley; 1998."},{"issue":"3","key":"519_CR13","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/nrd1032","volume":"2","author":"H van de Waterbeemd","year":"2003","unstructured":"van de Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov. 2003;2(3):192\u2013204. https:\/\/doi.org\/10.1038\/nrd1032.","journal-title":"Nat Rev Drug Discov"},{"issue":"4","key":"519_CR14","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/S1093-3263(01)00123-1","volume":"20","author":"A Golbraikh","year":"2002","unstructured":"Golbraikh A, Tropsha A. Beware of q2! J Mol Graph Model. 2002;20(4):269\u201376. https:\/\/doi.org\/10.1016\/S1093-3263(01)00123-1.","journal-title":"J Mol Graph Model"},{"issue":"4","key":"519_CR15","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1021\/ci0203702","volume":"42","author":"DK Agrafiotis","year":"2002","unstructured":"Agrafiotis DK, Cede\u00f1o W, Lobanov VS. On the use of neural network ensembles in QSAR and QSPR. J Chem Inf Comput Sci. 2002;42(4):903\u201311. https:\/\/doi.org\/10.1021\/ci0203702.","journal-title":"J Chem Inf Comput Sci"},{"issue":"9","key":"519_CR16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0204532","volume":"13","author":"D Sbrissa","year":"2018","unstructured":"Sbrissa D, Naisan G, Ikonomov OC, Shisheva A. Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation. PLoS One. 2018;13(9):e0204532. https:\/\/doi.org\/10.1371\/journal.pone.0204532.","journal-title":"PLoS One"},{"issue":"1","key":"519_CR17","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1758-2946-6-34","volume":"6","author":"RD Clark","year":"2014","unstructured":"Clark RD, Liang W, Lee AC, Lawless MS, Fraczkiewicz R, Waldman M. Using beta binomials to estimate classification uncertainty for ensemble models. J Cheminform. 2014;6(1):34. https:\/\/doi.org\/10.1186\/1758-2946-6-34.","journal-title":"J Cheminform"},{"issue":"1","key":"519_CR18","doi-asserted-by":"publisher","first-page":"46277","DOI":"10.1038\/srep46277","volume":"7","author":"D Lagorce","year":"2017","unstructured":"Lagorce D, Douguet D, Miteva MA, Villoutreix BO. Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors. Sci Rep. 2017;7(1):46277. https:\/\/doi.org\/10.1038\/srep46277.","journal-title":"Sci Rep"},{"key":"519_CR19","unstructured":"ADMET Predictor. Lancaster: Simulations Plus, Inc.; 2019. https:\/\/www.simulations-plus.com."},{"key":"519_CR20","unstructured":"ADMET. Predictor manual. Toxicity Module. https:\/\/www.simulations-plus.com\/software\/admetpredictor\/toxicity\/."},{"issue":"9","key":"519_CR21","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.1002\/ps.4935","volume":"74","author":"RD Clark","year":"2018","unstructured":"Clark RD. Predicting mammalian metabolism and toxicity of pesticides in silico. Pest Manag Sci. 2018;74(9):1992\u20132003. https:\/\/doi.org\/10.1002\/ps.4935.","journal-title":"Pest Manag Sci"},{"issue":"11","key":"519_CR22","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1021\/jm0205651","volume":"46","author":"R Pearlstein","year":"2003","unstructured":"Pearlstein R, Vaz R, Rampe D. Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior. J Med Chem. 2003;46(11):2017\u201322. https:\/\/doi.org\/10.1021\/jm0205651.","journal-title":"J Med Chem"},{"issue":"7083","key":"519_CR23","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nature04710","volume":"440","author":"MC Sanguinetti","year":"2006","unstructured":"Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006;440(7083):463\u20139. https:\/\/doi.org\/10.1038\/nature04710.","journal-title":"Nature."},{"issue":"5","key":"519_CR24","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1021\/ci300112j","volume":"52","author":"D Cao","year":"2012","unstructured":"Cao D, Wang J, Zhou R, Li Y, Yu H, Hou T. ADMET evaluation in drug discovery. 11. PharmacoKinetics Knowledge Base (PKKB): a comprehensive database of pharmacokinetic and toxic properties for drugs. J Chem Inf Model. 2012;52(5):1132\u20137. https:\/\/doi.org\/10.1021\/ci300112j.","journal-title":"J Chem Inf Model"},{"key":"519_CR25","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1145\/2939672.2939785","volume-title":"Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining","author":"T Chen","year":"2016","unstructured":"Chen T, Guestrin C. XGBoost: a Scalable Tree Boosting System. In: Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining; 2016. p. 785\u201394. https:\/\/doi.org\/10.1145\/2939672.2939785."},{"key":"519_CR26","volume-title":"RDKit documentation","author":"G Landrum","year":"2019","unstructured":"Landrum, G. RDKit documentation. 2019. http:\/\/www.rdkit.org\/."},{"key":"519_CR27","unstructured":"ADMET predictor- Metabolism Module. https:\/\/www.simulations-plus.com\/software\/admetpredictor\/metabolism\/."},{"key":"519_CR28","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.comtox.2017.05.001","volume":"6","author":"S Wacker","year":"2018","unstructured":"Wacker S, Noskov SY. Performance of machine learning algorithms for qualitative and quantitative prediction drug blockade of hERG1 channel. Comput Toxicol. 2018;6:55\u201363. https:\/\/doi.org\/10.1016\/j.comtox.2017.05.001.","journal-title":"Comput Toxicol"},{"issue":"3","key":"519_CR29","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1007\/BF00173538","volume":"346","author":"E Nissinen","year":"1992","unstructured":"Nissinen E, Lind\u00e9n IB, Schultz E, Pohto P. Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone. Naunyn Schmiedeberg's Arch Pharmacol. 1992;346(3):262\u20136. https:\/\/doi.org\/10.1007\/BF00173538.","journal-title":"Naunyn Schmiedeberg's Arch Pharmacol"},{"issue":"3","key":"519_CR30","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/s002280050448","volume":"54","author":"C De Santi","year":"1998","unstructured":"De Santi C, Giulianotti PC, Pietrabissa A, Mosca F, Pacifici GM. Catechol-O-methyltransferase: variation in enzyme activity and inhibition by entacapone and tolcapone. Eur J Clin Pharmacol. 1998;54(3):215\u20139. https:\/\/doi.org\/10.1007\/s002280050448.","journal-title":"Eur J Clin Pharmacol"},{"issue":"25","key":"519_CR31","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/newbio231232a0","volume":"231","author":"JR Vane","year":"1971","unstructured":"Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231(25):232\u20135. https:\/\/doi.org\/10.1038\/newbio231232a0.","journal-title":"Nat New Biol"},{"issue":"2","key":"519_CR32","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1111\/head.12769","volume":"56","author":"S Lucas","year":"2016","unstructured":"Lucas S. The Pharmacology of Indomethacin. Headache. 2016;56(2):436\u201346. https:\/\/doi.org\/10.1111\/head.12769.","journal-title":"Headache"},{"key":"519_CR33","doi-asserted-by":"crossref","unstructured":"Ravichandran R, Purna P, Vijayaragavan S, Kalavakollu RT, Gaidhane S, Kumar RK. Efficacy and Safety of Indomethacin in Covid-19 patients. medRxiv. 2020; 2020.12.14.20245266.","DOI":"10.1101\/2020.12.14.20245266"},{"issue":"8","key":"519_CR34","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1177\/135965350601100803","volume":"11","author":"C Amici","year":"2006","unstructured":"Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021\u201330.","journal-title":"Antivir Ther"},{"issue":"6","key":"519_CR35","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/S0006-2952(98)00336-0","volume":"57","author":"A Michaud","year":"1999","unstructured":"Michaud A, Chauvet M, Corvol P. N-domain selectivity of angiotensin I-converting enzyme as assessed by structure-function studies of its highly selective substrate, N-acetyl-seryl-aspartyl-lysyl-proline. Biochem Pharmacol. 1999;57(6):611\u20138. https:\/\/doi.org\/10.1016\/S0006-2952(98)00336-0.","journal-title":"Biochem Pharmacol"},{"issue":"3","key":"519_CR36","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1042\/CS20201511","volume":"135","author":"MA Pedrosa","year":"2021","unstructured":"Pedrosa MA, Valenzuela R, Garrido-Gil P, Labandeira CM, Navarro G, Franco R, et al. Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19. Clin Sci. 2021;135(3):465\u201381. https:\/\/doi.org\/10.1042\/CS20201511.","journal-title":"Clin Sci"},{"issue":"6","key":"519_CR37","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/s41581-020-0279-4","volume":"16","author":"AM South","year":"2020","unstructured":"South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020;16(6):305\u20137. https:\/\/doi.org\/10.1038\/s41581-020-0279-4.","journal-title":"Nat Rev Nephrol"},{"issue":"4","key":"519_CR38","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.jemermed.2020.04.004","volume":"58","author":"C Eastin","year":"2020","unstructured":"Eastin C, Eastin T. Clinical characteristics of coronavirus disease 2019 in China: Guan W, Ni Z, Hu Y, et al. N Engl J Med. 2020 Feb 28 [Online ahead of print] DOI: 10.1056\/NEJMoa2002032. J Emerg Med. 2020;58(4):711\u20132. https:\/\/doi.org\/10.1016\/j.jemermed.2020.04.004.","journal-title":"J Emerg Med"},{"key":"519_CR39","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.urology.2020.04.057","volume":"141","author":"CS Biyani","year":"2020","unstructured":"Biyani CS, Palit V, Daga S. The use of captopril\u2014angiotensin converting enzyme (ACE) inhibitor for Cystinuria during COVID-19 pandemic. Urology. 2020;141:182\u20133. https:\/\/doi.org\/10.1016\/j.urology.2020.04.057.","journal-title":"Urology."},{"issue":"6","key":"519_CR40","doi-asserted-by":"publisher","first-page":"2042","DOI":"10.1128\/AAC.01411-05","volume":"50","author":"EE McKee","year":"2006","unstructured":"McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother. 2006;50(6):2042\u20139. https:\/\/doi.org\/10.1128\/AAC.01411-05.","journal-title":"Antimicrob Agents Chemother"},{"issue":"5","key":"519_CR41","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.ccr.2011.10.015","volume":"20","author":"M Skrti\u0107","year":"2011","unstructured":"Skrti\u0107 M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, et al. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell. 2011;20(5):674\u201388. https:\/\/doi.org\/10.1016\/j.ccr.2011.10.015.","journal-title":"Cancer Cell"},{"key":"519_CR42","doi-asserted-by":"publisher","unstructured":"Gonzalez-Zorn B. Antibiotic use in the COVID-19 crisis in Spain. Clin Microbiol Infect. 2021. https:\/\/doi.org\/10.1016\/j.cmi.2020.09.055.","DOI":"10.1016\/j.cmi.2020.09.055"},{"key":"519_CR43","doi-asserted-by":"publisher","unstructured":"Moghadam VD, Momenimovahed Z, Ghorbani M, Khodadadi J. Linezolid a Potential treatment for COVID-19 Co-Infections. Braz J Anesthesiol. 2021. https:\/\/doi.org\/10.1016\/j.bjane.2020.12.019.","DOI":"10.1016\/j.bjane.2020.12.019"},{"issue":"24","key":"519_CR44","doi-asserted-by":"publisher","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","volume":"20","author":"M G\u00f6ttlicher","year":"2001","unstructured":"G\u00f6ttlicher M, Minucci S, Zhu P, Kr\u00e4mer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20(24):6969\u201378. https:\/\/doi.org\/10.1093\/emboj\/20.24.6969.","journal-title":"EMBO J"},{"issue":"13","key":"519_CR45","doi-asserted-by":"publisher","first-page":"3411","DOI":"10.1093\/emboj\/cdg315","volume":"22","author":"OH Kr\u00e4mer","year":"2003","unstructured":"Kr\u00e4mer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003;22(13):3411\u201320. https:\/\/doi.org\/10.1093\/emboj\/cdg315.","journal-title":"EMBO J"},{"issue":"1","key":"519_CR46","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1021\/ml1001954","volume":"2","author":"DM Fass","year":"2010","unstructured":"Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao W-N, et al. Effect of inhibiting histone deacetylase with short-chain carboxylic acids and their Hydroxamic acid analogs on vertebrate development and neuronal chromatin. ACS Med Chem Lett. 2010;2(1):39\u201342. https:\/\/doi.org\/10.1021\/ml1001954.","journal-title":"ACS Med Chem Lett"},{"issue":"1","key":"519_CR47","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/0006-8993(82)90664-3","volume":"240","author":"EJ Hammond","year":"1982","unstructured":"Hammond EJ, Perchalski RJ, Villarreal HJ, Wilder BJ. In vivo uptake of valproic acid into brain. Brain Res. 1982;240(1):195\u20138. https:\/\/doi.org\/10.1016\/0006-8993(82)90664-3.","journal-title":"Brain Res"},{"key":"519_CR48","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann M, Kleine-Weber H, Schroeder S, Kr\u00fcger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271\u2013280.e8.","journal-title":"Cell"},{"issue":"10234","key":"519_CR49","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","volume":"395","author":"Z Varga","year":"2020","unstructured":"Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417\u20138. https:\/\/doi.org\/10.1016\/S0140-6736(20)30937-5.","journal-title":"Lancet."},{"key":"519_CR50","first-page":"138","volume":"19","author":"S Singh","year":"2020","unstructured":"Singh S. Valproic acid in prevention and treatment of COVID. Int J Respir Pulm Med. 2020;19:138.","journal-title":"Int J Respir Pulm Med"},{"issue":"5","key":"519_CR51","first-page":"450","volume":"57","author":"X-H Yang","year":"2007","unstructured":"Yang X-H, Deng W, Tong Z, Liu Y-X, Zhang L-F, Zhu H, et al. Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med. 2007;57(5):450\u20139.","journal-title":"Comp Med"},{"issue":"6965","key":"519_CR52","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/nature02145","volume":"426","author":"W Li","year":"2003","unstructured":"Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450\u20134. https:\/\/doi.org\/10.1038\/nature02145.","journal-title":"Nature."},{"issue":"6","key":"519_CR53","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1161\/01.HYP.0000146120.29648.36","volume":"44","author":"MJ Huentelman","year":"2004","unstructured":"Huentelman MJ, Zubcevic J, Hern\u00e1ndez Prada JA, Xiao X, Dimitrov DS, Raizada MK, et al. Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor. Hypertension. 2004;44(6):903\u20136. https:\/\/doi.org\/10.1161\/01.HYP.0000146120.29648.36.","journal-title":"Hypertension."},{"issue":"8","key":"519_CR54","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/nm1267","volume":"11","author":"K Kuba","year":"2005","unstructured":"Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875\u20139. https:\/\/doi.org\/10.1038\/nm1267.","journal-title":"Nat Med"},{"key":"519_CR55","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.jaci.2020.05.008","volume":"146","author":"T Herold","year":"2020","unstructured":"Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146:128\u2013136.e4.","journal-title":"J Allergy Clin Immunol"},{"key":"519_CR56","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1146\/annurev.med.47.1.315","volume":"47","author":"KK Wu","year":"1996","unstructured":"Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med. 1996;47:315\u201331. https:\/\/doi.org\/10.1146\/annurev.med.47.1.315.","journal-title":"Annu Rev Med"},{"issue":"5","key":"519_CR57","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1111\/j.1365-3083.2008.02029.x","volume":"67","author":"V Videm","year":"2008","unstructured":"Videm V, Albrigtsen M. Soluble ICAM-1 and VCAM-1 as markers of endothelial activation. Scand J Immunol. 2008;67(5):523\u201331. https:\/\/doi.org\/10.1111\/j.1365-3083.2008.02029.x.","journal-title":"Scand J Immunol"},{"key":"519_CR58","doi-asserted-by":"publisher","unstructured":"Unal G, Turan B, Balcioglu YH. Immunopharmacological management of COVID-19: potential therapeutic role of valproic acid. Med Hypotheses. 2020;143:\u2013109891. https:\/\/doi.org\/10.1016\/j.mehy.2020.109891.","DOI":"10.1016\/j.mehy.2020.109891"},{"key":"519_CR59","doi-asserted-by":"publisher","first-page":"726","DOI":"10.3389\/fchem.2020.00726","volume":"8","author":"F Wu","year":"2020","unstructured":"Wu F, Zhou Y, Li L, Shen X, Chen G, Wang X, et al. Computational approaches in preclinical studies on drug discovery and development. Front Chem. 2020;8:726. https:\/\/doi.org\/10.3389\/fchem.2020.00726.","journal-title":"Front Chem"},{"issue":"2","key":"519_CR60","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/wcms.1240","volume":"6","author":"AB Raies","year":"2016","unstructured":"Raies AB, Bajic VB. In silico toxicology: computational methods for the prediction of chemical toxicity. Wiley Interdiscip Rev Comput Mol Sci. 2016;6(2):147\u201372. https:\/\/doi.org\/10.1002\/wcms.1240.","journal-title":"Wiley Interdiscip Rev Comput Mol Sci"}],"container-title":["BMC Pharmacology and Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40360-021-00519-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40360-021-00519-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40360-021-00519-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T22:46:49Z","timestamp":1673563609000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpharmacoltoxicol.biomedcentral.com\/articles\/10.1186\/s40360-021-00519-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,21]]},"references-count":60,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["519"],"URL":"https:\/\/doi.org\/10.1186\/s40360-021-00519-5","relation":{},"ISSN":["2050-6511"],"issn-type":[{"value":"2050-6511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,21]]},"assertion":[{"value":"8 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"61"}}